Proctor2008 - p53/Mdm2 circuit - p53 stablisation by p14ARF

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Model Identifier
BIOMD0000000189
Short description
Proctor2008 - p53/Mdm2 circuit - p53 stabilisation by p14ARF

This model is described in the article:

Proctor CJ, Gray DA.
BMC Syst Biol 2008; 2: 75

Abstract:

BACKGROUND: In individual living cells p53 has been found to be expressed in a series of discrete pulses after DNA damage. Its negative regulator Mdm2 also demonstrates oscillatory behaviour. Attempts have been made recently to explain this behaviour by mathematical models but these have not addressed explicit molecular mechanisms. We describe two stochastic mechanistic models of the p53/Mdm2 circuit and show that sustained oscillations result directly from the key biological features, without assuming complicated mathematical functions or requiring more than one feedback loop. Each model examines a different mechanism for providing a negative feedback loop which results in p53 activation after DNA damage. The first model (ARF model) looks at the mechanism of p14ARF which sequesters Mdm2 and leads to stabilisation of p53. The second model (ATM model) examines the mechanism of ATM activation which leads to phosphorylation of both p53 and Mdm2 and increased degradation of Mdm2, which again results in p53 stabilisation. The models can readily be modified as further information becomes available, and linked to other models of cellular ageing. RESULTS: The ARF model is robust to changes in its parameters and predicts undamped oscillations after DNA damage so long as the signal persists. It also predicts that if there is a gradual accumulation of DNA damage, such as may occur in ageing, oscillations break out once a threshold level of damage is acquired. The ATM model requires an additional step for p53 synthesis for sustained oscillations to develop. The ATM model shows much more variability in the oscillatory behaviour and this variability is observed over a wide range of parameter values. This may account for the large variability seen in the experimental data which so far has examined ARF negative cells. CONCLUSION: The models predict more regular oscillations if ARF is present and suggest the need for further experiments in ARF positive cells to test these predictions. Our work illustrates the importance of systems biology approaches to understanding the complex role of p53 in both ageing and cancer.

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Format
SBML (L2V3)
Related Publication
  • Explaining oscillations and variability in the p53-Mdm2 system.
  • Carole J Proctor, Douglas A Gray
  • BMC systems biology , 8/ 2008 , Volume 2 , pages: 75 , PubMed ID: 18706112
Contributors
Submitter of the first revision: Carole Proctor
Submitter of this revision: Lucian Smith
Curator: Lucian Smith
Modeller: Carole Proctor

Metadata information

is (2 statements)
BioModels Database BIOMD0000000189
BioModels Database MODEL8142536273

isDescribedBy (1 statement)
PubMed 18706112

hasTaxon (1 statement)
Taxonomy Homo sapiens

isVersionOf (1 statement)
isPartOf (2 statements)
hasProperty (1 statement)
Mathematical Modelling Ontology Ordinary differential equation model


Curation status
Curated


Connected external resources